The majority of our work in the past year has concerned the disposition and metabolism of n-butyl glycidyl ether (BGE). BGE is a high production chemical used primarily in epoxy-based resins and adhesives. While the most common epoxy resins are composed of bis-phenol A and epichlorohydrin, they may contain other phenols or epoxides to modify their properties. BGE is being studied by the National Toxicology Program as an example of the aliphatic glycidyl ether class of epoxy components. The disposition of 14C-labeled BGE, was studied in rats and mice. The majority of a single oral dose (2-200 mg/kg) was excreted in urine (rats, 84-92%; mice, 64-73%) within 24 h. The rest of the dose was excreted in feces (rats, 2.6-7.7%; mice 5.3-12%) and in expired air as 14CO2 (rats, 1.5%; mice 10-18%), or remained in the tissues (rats, 2.7-4.4%; mice, 1.5-1.7%). No parent BGE was detected in rat or mouse urine. Fifteen urinary metabolites were identified, including 3-butoxy-2-hydroxy-1-propanol and its mono-sulfate or mono-glucuronide conjugates, 3-butoxy-2-hydroxypropionic acid, O-butyl-N-acetylserine, butoxyacetic acid, 2-butoxyethanol, and 3-butoxy-1-(N-acetylcystein-S-yl)-2-propanol, the mercapturic acid metabolite derived from conjugation of GSH with BGE at the C-1 position. Some of these metabolites underwent further &#969;-1 oxidation to form a 3-hydroxybutoxy substitution. One urinary metabolite was from &#969;-oxidation of 3-butoxy-1-(N-acetylcystein-S-yl)-2-propanol to yield the corresponding carboxylic acid. Oxidative deamination of 3-butoxy-1-(cystein-S-yl)-2-propanol gave the corresponding &#945;-keto acid and &#945;-hydroxy acid metabolites that were present in mouse urine but not in rat urine. An in vitro incubation of BGE with GSH showed that the conjugation occurred only at the C-1 position with or without the addition of glutathione S-transferase. Butoxyacetic acid, one of the BGE metabolites, is considered to be responsible for the erythrotoxicity of butoxyethanol. There was neither evidence of enhanced uptake of 14C by erythrocytes, nor any evidence of erythrotoxicity from the BGE-treated animals.[unreadable] [unreadable] We have had a long-term interest in the metabolism of furans. This 5-membered heterocycle is found in natural products and is generally considered a structural alert for toxicity. Furans are metabolized by cytochromes P450 either to an epoxide or to a ring-opened intermediate consisting of two carbonyl groups substituted on either end of a vinyl group (O=C-C=C-C=O, dioxabutene). We reported the in vitro metabolism of 4-ipomeanol and ipomeanine, furan-containing natural products, last year. By using d6-dimethyldioxirane in d6-acetone the dioxabutene intermediate could be detected by NMR spectroscopy. In vitro oxidation with hepatic microsomes in the presence of glutathione led to adducts in which as many as 3 new bonds were formed between the reactive intermediate and GSH. In light of the toxicity generally observed with furans, we were curious about the lack of toxicity associated with furosemide (Lasix). This furan-containing drug has been in use for decades with few problems. Metabolism studies to date have offered few clues for the lack of toxicity. Our experience with dimethyldioxirane oxidation of other furans led us to try oxidizing furosemide in the d6-dimethyldoxirane/acetone system. The NMR spectrum of the reaction product contained no signals attributable to the dioxabutene, instead the first observable signals were from a product of the secondary amine in furosemide and the dioxabutene. This intramolecular reaction is fast allowing no build-up of the reactive intermediate. This likely is the explanation for the lack of toxicity of the drug. Thus ends our study of furan metabolism and ES0210-75: xenobiotic Metabolism.